2
Topics Process what is EUCAST? what does it do? why does it do it? what are the advantages? (if any), Do I care? Definitions  clinical breakpoints and wild type cut offs  categorical results (S, R, I)  non- species specific breakpoints How a clinical breakpoint is assessed/decided Changes in BSAC breakpoints so far The future Summary

3
EUCAST Is - European Committee on Antimicrobial Susceptibility Testing formed in 1997, restructured into present form in 2002 convened by – European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and National Breakpoint Committees of Europe (France, CA-SFM; Germany; DIN; Netherlands, CRG; Norway, NWGA; Sweden, SRGA; UK, BSAC WP) Financed by – ESCMID National Committees DG-SANCO of the EU for 3years until May 07

4
EUCAST objectives  set common European antimicrobial breakpoints for surveillance  to harmonise breakpoints for existing and new drugs (all agents)  (promote standardisation of methodologies)  (encourage I and E QA)  (collaborate with other groups in AST and epidemiology)  advise EU institutions  (training)

5
EUCAST General Committee  one representative of each European country (n=32), ISC and FESCI (n=2)  Chair/Scientific Secretary/Clinical Co-ordinator (n=3) appointed by ECCMD Steering Committee  one representative of each European national breakpoint committee (n=6)  two representatives of the EUCAST General Committee.  Chair/Scientific Secretary/Clinical Co-ordinator (as above)

8
Advantages of the EUCAST process for BSAC users vigorous process for reviewing clinical breakpoints based on pK, pD, MIC distributions, clinical trials, medical experience. consultation with 5 other National Committees and open consultation across Europe. harmonised breakpoints for old agents improved data (pK, pD, MIC, clinical trial) for new agents - link with EMEA improved international acceptance of UK breakpoints epidemiological advantages reduced dependency on CLSI/NCCLS and FDA

9
Definitions Clinical breakpoints susceptible a micro organism is defined as susceptible of inhibited in vitro by a concentration of an antimicrobial agent that is associated with a high likelihood of therapeutic success. Resistant a micro organism is defined as resistant if inhibited in vitro by a concentration of an antimicrobial agent that is associated with a high likelihood of therapeutic failure

10
Definitions – cont’d Intermediate a micro organism is defined as intermediate by a level of antimicrobial agent activity associated with uncertain effect. It implies –  infection may be treated in body sites where the drug is concentrated or, when a high dosage can be used.  it indicates a buffer zone to prevent small uncontrolled technical factors causing major discrepancies in interpretation.

11
The intermediate category (I)  re-introduction for BSAC users (previous M is Stoke’s methodology).  most other breakpoint committees have I category.  until now I and R combined in BSAC methodology - both called R.  usually a doubling tube dilution higher than S/I breakpoint.

12
What does intermediate mean? All things to all men? if drug is concentrated at a body site, can use the I/R breakpoint to define susceptibility, example urinary testing for uncomplicated UTI. Problems: definitions of tissue penetration : most bps based on blood levels for the treatment of tissue infection : little evidence to support an I/R breakpoint

13
Intermediate - cont’d if you can use a bigger dose, novel dosing strategy this will overcome the resistance level. Twice the dose, doubles the clinical breakpoint also could add a second agent to overcome low level resistance e.g. P. aeruginosa therapy with meropenem if MIC 2-8mg/L problems -emergence of resistance may be more common: efflux mutants and fluoroquinolones -what if the mechanism is an enzyme in contrast to efflux pump or target site mutation

16
Is the intermediate category a useful adjunct Yes because:- allows consideration of high dose, addition of a second agent, novel dosing. (much more data needed, i.e. MIC value) allows consideration of tissue penetration (be very careful) allows a blunder zone can continue to lump I/R together for epidemiological purposes Main problems:- understanding what I means at a clinical level coping with S/I/R in epidemiological capture of laboratory data others

17
Epidemiological cut of values a micro organism is defined as wild type (WT) by the absence of acquired or mutational resistance mechanisms WT is presented as WT < Xmg/L Wild type organisms may or may not respond clinically to antimicrobial treatment

18
Graph shown in the EUCAST program for display of MIC distributions of wild type bacteria. Values >1% show on graph!

19
Non species specific breakpoint (clinical breakpoint) -these are determined on the basis of Pharmacokinetic/ Pharmacodynamic data and are independent of MIC distributions of any bacterial species. They may be used only for species that have not been given a clinical breakpoint.

20
Relevant factors in setting clinical breakpoints national similarities and differences regarding dosing and dose size national differences in target organisms dose/concentration effect relationships in animals, in vitro and man (pK/pD data). modelling process such as Monte Carlo simulation may be used to assess breakpoints clinical outcome data related to MICs, drug exposures and pD indices breakpoints are tested against MIC distribution data to ensure wild type MIC distributions not split consensus is sought through the General Committee and National Committees

29
”Dashed” – laboratories are recommended not to test against this species Click on name to directly access MIC distributions Insufficient evidence EUCAST breakpoint tables available at http://www.eucast.org

36
The future  complete set of clinical breakpoints and wild type cut offs based on European process (EUCAST)  mapping of breakpoints into standard methods (France, Norway, Sweden, UK)  ?standardised methodologies ISO/SEN standard for MIC testing  relationship with EMEA means EUCAST will set breakpoints for new agents in Europe and for new drug SPC  relationship with CLSI/NCCLS

37
Summary  EUCAST is a functional EU funded national collaboration!  Professionally based  improved credibility for UK clinical breakpoints  improved cross Europe epidemiology  some different concepts for BSAC users: I, wild type cut offs, non-species specific breakpoints  some different breakpoints but less direct impact than you may think  major focus for BSAC in medium term is on implementation/ education